Give lipids a START: the StAR-related lipid transfer (START) domain in mammals

The steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain is a protein module of ∼210 residues that binds lipids, including sterols. Fifteen mammalian proteins, STARD1-STARD15, possess a START domain and these can be grouped into six subfamilies. Cholesterol, 25-hydroxycholesterol, phosphatidylcholine, phosphatidylethanolamine and ceramides are ligands for STARD1/STARD3/STARD5, STARD5, STARD2/STARD10, STARD10 and STARD11, respectively. The lipids or sterols bound by the remaining 9 START proteins are unknown. Recent studies show that the C-terminal end of the domain plays a fundamental role, forming a lid over a deep lipid-binding pocket that shields the ligand from the external environment. The START domain can be regarded as a lipid-exchange and/or a lipid-sensing domain. Mammalian START proteins have diverse expression patterns and can be found free in the cytoplasm, attached to membranes or in the nucleus. They appear to function in a variety of distinct physiological processes, such as lipid transfer between intracellular compartments, lipid metabolism and modulation of signaling events. Mutation or misexpression of START proteins is linked to pathological processes, including genetic disorders, autoimmune disease and cancer.

[1]  J. Thompson,et al.  CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. , 1994, Nucleic acids research.

[2]  S. King,et al.  The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). , 1994, The Journal of biological chemistry.

[3]  Flemming M. Poulsen,et al.  X-ray and NMR structure of Bet v 1, the origin of birch pollen allergy , 1996, Nature Structural Biology.

[4]  Christian A. Rees,et al.  Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[5]  H. Nojima,et al.  Molecular Cloning and Characterization of Phosphatidylcholine Transfer Protein-Like Protein Gene Expressed in Murine Haploid Germ Cells , 2000, Biology of reproduction.

[6]  J. Hurley,et al.  Structure and lipid transport mechanism of a StAR-related domain , 2000, Nature Structural Biology.

[7]  S. Thorgeirsson,et al.  DLC-1 operates as a tumor suppressor gene in human non-small cell lung carcinomas , 2004, Oncogene.

[8]  S. Munro,et al.  Targeting of Golgi-Specific Pleckstrin Homology Domains Involves Both PtdIns 4-Kinase-Dependent and -Independent Components , 2002, Current Biology.

[9]  J. Forteza,et al.  Goodpasture Antigen-binding Protein, the Kinase That Phosphorylates the Goodpasture Antigen, Is an Alternatively Spliced Variant Implicated in Autoimmune Pathogenesis* , 2000, The Journal of Biological Chemistry.

[10]  Nils Brose,et al.  Move over protein kinase C, you've got company: alternative cellular effectors of diacylglycerol and phorbol esters , 2002, Journal of Cell Science.

[11]  H. Kamata,et al.  A PLCdelta1-binding protein, p122RhoGAP, is localized in focal adhesions. , 2004, Biochemical Society transactions.

[12]  P. Basset,et al.  MLN64 exhibits homology with the steroidogenic acute regulatory protein (STAR) and is over‐expressed in human breast carcinomas , 1997, International journal of cancer.

[13]  F. Revert,et al.  Characterization of a Novel Type of Serine/Threonine Kinase That Specifically Phosphorylates the Human Goodpasture Antigen* , 1999, The Journal of Biological Chemistry.

[14]  S. Thorgeirsson,et al.  Cloning, characterization, and chromosomal localization of a gene frequently deleted in human liver cancer (DLC-1) homologous to rat RhoGAP. , 1998, Cancer research.

[15]  S. Colman,et al.  BFIT, a unique acyl-CoA thioesterase induced in thermogenic brown adipose tissue: cloning, organization of the human gene and assessment of a potential link to obesity. , 2001, The Biochemical journal.

[16]  G. M. Nagaraja,et al.  Chromosome 13q12 encoded Rho GTPase activating protein suppresses growth of breast carcinoma cells, and yeast two-hybrid screen shows its interaction with several proteins. , 2004, Biochemical and biophysical research communications.

[17]  P. Brown,et al.  Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[18]  José A. Poveda,et al.  Binding of the C-terminal Sterile α Motif (SAM) Domain of Human p73 to Lipid Membranes* , 2003, Journal of Biological Chemistry.

[19]  S. Munro.  Cell biology: Earthworms and lipid couriers , 2003, Nature.

[20]  Rachel M. Adams,et al.  Differential Gene Regulation of StarD4 and StarD5 Cholesterol Transfer Proteins , 2005, Journal of Biological Chemistry.

[21]  V. Lingappa,et al.  Rapid regulation of steroidogenesis by mitochondrial protein import , 2002, Nature.

[22]  D. Pain,et al.  Steroidogenic acute regulatory protein (StAR) retains activity in the absence of its mitochondrial import sequence: implications for the mechanism of StAR action. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[23]  T. Barrette,et al.  ONCOMINE: a cancer microarray database and integrated data-mining platform. , 2004, Neoplasia.

[24]  A. Travis,et al.  The role of cholesterol efflux in regulating the fertilization potential of mammalian spermatozoa. , 2002, The Journal of clinical investigation.

[25]  D. Stocco.  StAR protein and the regulation of steroid hormone biosynthesis. , 2001, Annual review of physiology.

[26]  A. Rogol,et al.  Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. , 1995, Science.

[27]  W. Wetsel,et al.  Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[28]  J. D. Bell,et al.  pH-dependent Interactions of the Carboxyl-terminal Helix of Steroidogenic Acute Regulatory Protein with Synthetic Membranes* , 2005, Journal of Biological Chemistry.

[29]  K. Hanada,et al.  Mammalian Cell Mutants Resistant to a Sphingomyelin-directed Cytolysin , 1998, The Journal of Biological Chemistry.

[30]  K. Schrick,et al.  START lipid/sterol-binding domains are amplified in plants and are predominantly associated with homeodomain transcription factors , 2004, Genome Biology.

[31]  M. Vetting,et al.  Structure of human phosphatidylcholine transfer protein in complex with its ligand , 2002, Nature Structural Biology.

[32]  Dong Zhao,et al.  Mitochondrial Processing of Newly Synthesized Steroidogenic Acute Regulatory Protein (StAR), but Not Total StAR, Mediates Cholesterol Transfer to Cytochrome P450 Side Chain Cleavage Enzyme in Adrenal Cells* , 2001, The Journal of Biological Chemistry.

[33]  M. Ringnér,et al.  Impact of DNA amplification on gene expression patterns in breast cancer. , 2002, Cancer research.

[34]  I. Tabas,et al.  Decreased lipid efflux and increased susceptibility to cholesterol-induced apoptosis in macrophages lacking phosphatidylcholine transfer protein. , 2005, The Biochemical journal.

[35]  C. Ponting,et al.  START: a lipid-binding domain in StAR, HD-ZIP and signalling proteins. , 1999, Trends in biochemical sciences.

[36]  Keesook Lee,et al.  Expression of the Putative Sterol Binding Protein Stard6 Gene Is Male Germ Cell Specific1 , 2005, Biology of reproduction.

[37]  S. Thorgeirsson,et al.  DLC-1 gene inhibits human breast cancer cell growth and in vivo tumorigenicity , 2003, Oncogene.

[38]  D. Stocco,et al.  Expression of the steroidogenic acute regulatory (StAR) protein: a novel LH-induced mitochondrial protein required for the acute regulation of steroidogenesis in mouse Leydig tumor cells. , 1995, Endocrine research.

[39]  D. Stocco,et al.  Involvement of multiple transcription factors in the regulation of steroidogenic acute regulatory protein gene expression , 2003, Steroids.

[40]  Yi Zheng,et al.  Rho GTPase-activating proteins in cell regulation. , 2003, Trends in cell biology.

[41]  P. Hylemon,et al.  Human StarD5, a cytosolic StAR-related lipid binding protein Published, JLR Papers in Press, May 16, 2005. DOI 10.1194/jlr.M400501-JLR200 , 2005, Journal of Lipid Research.

[42]  J. Hanover,et al.  MLN64 Mediates Mobilization of Lysosomal Cholesterol to Steroidogenic Mitochondria* 210 , 2002, The Journal of Biological Chemistry.

[43]  C. Thiele,et al.  Functional Characterization of the MENTAL Domain* , 2005, Journal of Biological Chemistry.

[44]  J. González-Ros,et al.  Binding of the C-terminal sterile alpha motif (SAM) domain of human p73 to lipid membranes. , 2003, The Journal of biological chemistry.

[45]  N. Suematsu,et al.  Molecular cloning and functional expression of rat liver cytosolic acetyl-CoA hydrolase. , 2001, European journal of biochemistry.

[46]  Satoshi Yasuda,et al.  Molecular machinery for non-vesicular trafficking of ceramide , 2003, Nature.

[47]  Stephen K. Burley,et al.  Crystal structure of the Mus musculus cholesterol-regulated START protein 4 (StarD4) containing a StAR-related lipid transfer domain , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[48]  I. Ng,et al.  Genetic and Epigenetic Alterations of DLC1 Gene in Hepatocellular Carcinoma , 2003 .

[49]  F. Isohashi,et al.  Effects of nucleotides on a cold labile acetyl-CoA hydrolase from the supernatant fraction of rat liver. , 1983, Biochemistry.

[50]  E. Lander,et al.  Gene expression correlates of clinical prostate cancer behavior. , 2002, Cancer cell.

[51]  Rachel M. Adams,et al.  The cholesterol-regulated StarD4 gene encodes a StAR-related lipid transfer protein with two closely related homologues, StarD5 and StarD6 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[52]  D. Cohen,et al.  High-level expression and mutagenesis of recombinant human phosphatidylcholine transfer protein using a synthetic gene: evidence for a C-terminal membrane binding domain. , 2000, Biochemistry.

[53]  I. Ng,et al.  Genetic and epigenetic alterations of DLC-1 gene in hepatocellular carcinoma. , 2003, Cancer research.

[54]  J. Holthuis,et al.  Lipid traffic: floppy drives and a superhighway , 2005, Nature Reviews Molecular Cell Biology.

[55]  Christopher J. R. Loewen,et al.  A conserved ER targeting motif in three families of lipid binding proteins and in Opi1p binds VAP , 2003, The EMBO journal.

[56]  K. Wirtz,et al.  Mice without phosphatidylcholine transfer protein have no defects in the secretion of phosphatidylcholine into bile or into lung airspaces. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[57]  M. Fujii,et al.  A PLCδ1‐binding protein, p122/RhoGAP, is localized in caveolin‐enriched membrane domains and regulates caveolin internalization , 2004, Genes to cells : devoted to molecular & cellular mechanisms.

[58]  Monilola A. Olayioye,et al.  StarD10, a START Domain Protein Overexpressed in Breast Cancer, Functions as a Phospholipid Transfer Protein*[boxs] , 2005, Journal of Biological Chemistry.

[59]  James U Bowie,et al.  SAM domains: uniform structure, diversity of function. , 2003, Trends in biochemical sciences.

[60]  D. Cohen,et al.  Phosphatidylcholine Transfer Protein Promotes Apolipoprotein A-I-mediated Lipid Efflux in Chinese Hamster Ovary Cells* , 2002, The Journal of Biological Chemistry.

[61]  H. Kamata,et al.  A PLCδ1-binding protein, p122RhoGAP, is localized in focal adhesions , 2004 .

[62]  A. Dierich,et al.  The Steroidogenic Acute Regulatory Protein Homolog MLN64, a Late Endosomal Cholesterol-binding Protein* , 2001, The Journal of Biological Chemistry.

[63]  H. Watari,et al.  MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[64]  S. Thorgeirsson,et al.  Restoration of DLC-1 gene expression induces apoptosis and inhibits both cell growth and tumorigenicity in human hepatocellular carcinoma cells , 2004, Oncogene.

[65]  P. Basset,et al.  Identification of four novel human genes amplified and overexpressed in breast carcinoma and localized to the q11-q21.3 region of chromosome 17. , 1995, Genomics.

[66]  M. Polymeropoulos,et al.  Gene expression profiling detects gene amplification and differentiates tumor types in breast cancer. , 2003, Cancer research.

[67]  F. Isohashi,et al.  Physiological changes in the activities of extramitochondrial acetyl-CoA hydrolase in the liver of rats under various metabolic conditions. , 1985, European journal of biochemistry.

[68]  S. Thorgeirsson,et al.  DLC‐1, a Rho GTPase‐activating protein with tumor suppressor function, is essential for embryonic development , 2005, FEBS letters.

[69]  S. Angeletti,et al.  GTT1/StarD7, a novel phosphatidylcholine transfer protein-like highly expressed in gestational trophoblastic tumour: cloning and characterization. , 2004, Placenta.

[70]  D. Stocco.  Clinical disorders associated with abnormal cholesterol transport: mutations in the steroidogenic acute regulatory protein , 2002, Molecular and Cellular Endocrinology.

[71]  M. Utter,et al.  Purification and characterization of an extramitochondrial acetyl coenzyme A hydrolase from rat liver. , 1980, The Journal of biological chemistry.

[72]  W. Miller,et al.  Binding of Steroidogenic Acute Regulatory Protein to Synthetic Membranes Suggests an Active Molten Globule* , 2001, The Journal of Biological Chemistry.

[73]  S. Yasuda,et al.  CERT Mediates Intermembrane Transfer of Various Molecular Species of Ceramides* , 2005, Journal of Biological Chemistry.

[74]  K. Wirtz,et al.  Clofibrate-induced relocation of phosphatidylcholine transfer protein to mitochondria in endothelial cells. , 2002, Experimental cell research.

[75]  S. Walkley,et al.  Targeted Mutation of the MLN64 START Domain Causes Only Modest Alterations in Cellular Sterol Metabolism* , 2004, Journal of Biological Chemistry.

[76]  W. Miller,et al.  Molten globule structure and steroidogenic activity of N-218 MLN64 in human placental mitochondria. , 2004, Endocrinology.

[77]  D. Driscoll,et al.  Human steroidogenic acute regulatory protein: functional activity in COS-1 cells, tissue-specific expression, and mapping of the structural gene to 8p11.2 and a pseudogene to chromosome 13. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[78]  I. Ng,et al.  DLC-1 is deleted in primary hepatocellular carcinoma and exerts inhibitory effects on the proliferation of hepatoma cell lines with deleted DLC-1. , 2000, Cancer research.

[79]  D. Botstein,et al.  Diversity of gene expression in adenocarcinoma of the lung , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[80]  Y. Jo,et al.  Multiple signaling pathways regulating steroidogenesis and steroidogenic acute regulatory protein expression: more complicated than we thought. , 2005, Molecular endocrinology.

[81]  E. Latulippe,et al.  Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease. , 2002, Cancer research.

[82]  I. Ng,et al.  Deleted in Liver Cancer (DLC) 2 Encodes a RhoGAP Protein with Growth Suppressor Function and Is Underexpressed in Hepatocellular Carcinoma* , 2003, The Journal of Biological Chemistry.

[83]  D. Botstein,et al.  Gene expression patterns in human liver cancers. , 2002, Molecular biology of the cell.

[84]  M. Baldwin,et al.  Evidence That Star and MLN64 act on the Outer Mitochondrial Membrane as Molten Globules , 2000, Endocrine research.

[85]  D. Lamb,et al.  The steroidogenic acute regulatory protein is expressed in steroidogenic cells of the day-old brain. , 2004, Endocrinology.

[86]  J. Breslow,et al.  StAR-related Lipid Transfer (START) Proteins: Mediators of Intracellular Lipid Metabolism* , 2003, Journal of Biological Chemistry.

[87]  Monilola A. Olayioye,et al.  The Phosphoprotein StarD10 Is Overexpressed in Breast Cancer and Cooperates with ErbB Receptors in Cellular Transformation , 2004, Cancer Research.

[88]  W. Paschen,et al.  Endoplasmic Reticulum Stress , 2007, Annals of the New York Academy of Sciences.

[89]  P. Neudecker,et al.  Solution Structure of the Major Cherry Allergen Pru av 1 , 2001 .

[90]  E. Koonin,et al.  Adaptations of the helix‐grip fold for ligand binding and catalysis in the START domain superfamily , 2001, Proteins.

[91]  S. Seitz,et al.  Analysis of DLC-1 expression in human breast cancer , 2003, Journal of Cancer Research and Clinical Oncology.

[92]  O. Monni,et al.  New amplified and highly expressed genes discovered in the ERBB2 amplicon in breast cancer by cDNA microarrays. , 2001, Cancer research.

[93]  W. Dowhan,et al.  Phospholipid-transfer proteins. , 1991, Current opinion in cell biology.

[94]  L. Saidi,et al.  Structural Mechanism for Lipid Activation of the Rac-Specific GAP, β2-Chimaerin , 2004, Cell.

[95]  F. Isohashi,et al.  Factors affecting the cold inactivation of an acetyl-coenzyme-A hydrolase purified from the supernatant fraction of rat liver. , 1983, European journal of biochemistry.

[96]  C. Tomasetto,et al.  MENTHO, a MLN64 Homologue Devoid of the START Domain* , 2002, The Journal of Biological Chemistry.

[97]  Y. Emori,et al.  Morphological Changes and Detachment of Adherent Cells Induced by p122, a GTPase-activating Protein for Rho* , 1999, The Journal of Biological Chemistry.

[98]  M. Durkin,et al.  Promoter hypermethylation of DLC-1, a candidate tumor suppressor gene, in several common human cancers. , 2003, Cancer genetics and cytogenetics.

[99]  Y. Emori,et al.  A dual functional signal mediator showing RhoGAP and phospholipase C‐delta stimulating activities. , 1995, The EMBO journal.

[100]  Naomi Melamed-Book,et al.  Proteolysis of normal and mutated steroidogenic acute regulatory proteins in the mitochondria: the fate of unwanted proteins. , 2003, Molecular endocrinology.

[101]  D. Stocco,et al.  Regulation of the acute production of steroids in steroidogenic cells. , 1996, Endocrine reviews.

[102]  Y. Jo,et al.  Multiple Signaling Pathways Regulating Steroidogenesis and StAR Expression: More Complicated Than We Thought , 2005 .